Effect of Obesity Paradox on Venous Thromboembolism Risk in Atrial Fib

A meta-analysis was conducted to examine concerns surrounding direct oral anticoagulant therapy in patients with extreme high or low body weight.

In a systematic review and meta-analysis published in the Journal of Thrombosis and Haemostasis, researchers found a paradoxical increase in thromboembolism risk in low-weight patients with atrial fibrillation (AF) and venous thromboembolism (VTE) who were treated with direct oral anticoagulants (DOACs).1

Although DOACs and warfarin are commonly prescribed to treat VTE and prevent systemic embolism in patients with AF, some clinicians have expressed concerns related to fixed dosage of DOACs, particularly in patients with extreme high or low body weight. It has been proposed that their efficacy may be reduced in patients with extremely high body weight, and that bleeding risk may be higher in those with extremely low body weight.

In the current study, Kochawan Boonyawat, MD, from the Department of Medicine at Ramathibodi Hospital at Mahidol University in Thailand, and colleagues examined these outcomes in patients taking DOACs and warfarin for acute VTE and AF. A body weight of ≤60 kg was considered low, and a minimum weight of 100 kg was considered high. Values between those extremes were defined as normal weight.

The analysis of 11 phase 3 randomized controlled trials showed an increased risk for thromboembolism in patients with low body weight vs those with non-low body weight (relative risk [RR], 1.57; 95% CI, 1.34-1.85). No association was observed between high body weight and thromboembolism risk compared with non-high body weight (RR, 0.88; 95% CI, 0.63-1.23).

The risk for thromboembolism was lower in a subgroup of patients with AF with high body weight vs non-high body weight (RR, 0.43; 95% CI, 0.28-0.67). There were similar bleeding outcomes across all body weights, and no clear interactions were found between anticoagulant types.

These findings (specifically, increased adverse outcomes in patients with lower body weight and more favorable outcomes in those with higher body weight) are in line with previous studies showing better cardiac outcomes in heavier patients, a phenomenon dubbed the “obesity paradox.”2-5 There are several possible explanations for these observations. For example, low body weight may result from chronic illnesses that are linked to increased thrombosis risk, and patients with higher body weight may be more closely monitored and optimally treated, leading to a reduced risk for adverse outcomes.

“These differences in thrombosis risk according to body weight were seen in both the DOAC and the comparison arms and were likely to be attributable to differences in other patient characteristics known to affect the baseline risk of thromboembolism, rather than the type of anticoagulant,” Dr Boonyawat and colleagues wrote. “We conclude that dose adjustment of DOACs, outside that recommended in the package insert, is unlikely to improve safety or efficacy.”

Study Limitations

  • Researchers were unable to adjust for baseline characteristics between the different body weight subgroups.
  • Observed associations do not demonstrate causation.
  • The meta-analysis included “very few” patients with high body weight; findings therefore do not apply to that patient population.
  • Body weight was measured at baseline, and changes in body weight were not accounted for.
  • Results “can only be applied with caution” to DOACs that use dose-adjustment per body weight.
  • Inconsistent body mass index/body weight reporting resulted in a differing number of studies used in each meta-analysis.
  • The researchers noted heterogeneity among thromboembolic outcomes in the high-body-weight comparison.

See the complete study for a full list of author disclosures. 

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  1. Boonyawat K, Caron F, Li A, et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis [published online May 9, 2017]. J Thromb Haemost. doi:10.1111/jth.13701
  2. Badheka AO, Rathod A, Kizilbash MA, et al. Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox. Am J Med. 2010;123(7):646-651. doi:10.1016/j.amjmed.2009.11.026
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